Project Summary Stroke is the leading cause of physical disability worldwide and represents a global socioeconomic burden to human health. Despite an intense research effort that led to a plethora of targets and neuroprotectants to reduce stroke-induced brain injury in animals, the neuroprotection-based strategies resulted in little or no efficacy in numerous controlled clinical trials. These observations indicate that there should be a paradigm shift to enhance the translational efficacy issue and improve this devastating condition. Potential missing links that account for the translational hindrances include solely relying on infarct size without considering brain swelling to gauge neuroprotection in preclinical studies. In addition, there is a paucity of inclusion of risk factors in animal models of stroke, whereas comorbidities such as dyslipidemia, hypertension, diabetes, and obesity are frequently observed conditions in patients. The combined evidence supports the conclusion that there is a critical need to define stroke pathology focusing on brain swelling in metabolically compromised conditions, which is the overall scientific premise for the proposed research. Our recent findings showed that mice with diabetes and hyperlipidemia displayed disproportionately larger brain swelling compared to infarct volume, and the enhanced brain swelling was closely associated with an increased level of vascular endothelial growth factor receptor 2 (VEGFR2), a key signaling molecule for vascular permeability and angiogenesis. As obesity is a precipitating cause leading to metabolic disorders including diabetes and dyslipidemia, we hypothesized that VEGFR2 underlies obesity-enhanced brain swelling in stroke and that blocking VEGFR2 activation reduces the swelling and promotes functional recovery in obesity. Aim 1 will identify the role of VEGFR2 activation(s) on stroke-induced brain swelling in obese mice by assessing histological and molecular outcomes. In Aim 2, the loss and gain of function studies will evaluate the efficacy of VEGFR2 modulation on obesity-enhanced stroke-induced brain swelling using pharmacological and genetic approaches. Aim 3 will determine the impact of brain swelling on long-term stroke recovery by assessing long-term motor and cognitive function in obese mice where VEGF signaling is manipulated. At the completion of the project, we expect to obtain scientific evidence establishing the importance of VEGF signaling in obesity-enhanced brain swelling, the utility of VEGF inhibition as a treatment strategy in obesity stroke, and reducing brain swelling as an approach to promoting long-term stroke recovery. These results are expected to have a significant impact by providing strong justification for the repurposing of available VEGF-targeted anti- angiogenic/anti-cancer drugs to treat stroke patients with obesity and its associated comorbidities.